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ABSTRACT Vancomycin-resistant E. faecium (VREfm) is a significant public health concern because of limited treatment options. Genomic surveillance can be used to monitor VREfm transmission and evolution. Genomic analysis of VREfm has not been reported for the Dallas/Fort Worth/Arlington, TX, area, which is currently the 4th largest metropolitan area in the United States. Our study aimed to address this gap in knowledge by analyzing the genomes of 46 VREfm strains and 1 vancomycin-sensitive comparator collected during routine fecal surveillance of high-risk patients upon admission to a Dallas, TX, hospital system (August to October 2015). Thirty-one complete and 16 draft genome sequences were generated. The closed VREfm genomes possessed up to 12 extrachromosomal elements each. Overall, 251 closed putative plasmid sequences assigned to previously described and newly defined rep family types were obtained. Phylogenetic analysis identified 10 different sequence types (STs) among the isolates, with the most prevalent being ST17 and ST18. Strikingly, all but three of the VREfm isolates encoded vanA-type vancomycin resistance within Tn1546-like elements on a pRUM-like (rep17) plasmid backbone. Relative to a previously reported typing scheme for the vanA-carrying Tn1546, new variants of the Tn1546 were identified that harbored a combination of 7 insertion sequences (IS), including 3 novel IS elements reported here (ISEfa16, ISEfa17, and ISEfa18). We conclude that pRUM-like plasmids are important vectors for vancomycin resistance in the Dallas, TX, area and should be a focus of plasmid surveillance efforts. IMPORTANCE Vancomycin is an antibiotic used to treat infections caused by multidrug-resistant Gram-positive bacteria. Vancomycin resistance is common in clinical isolates of the Gram-positive pathogen Enterococcus faecium. Among E. faecium strains, vancomycin resistance genes can be disseminated by plasmids with different host ranges and transfer efficiencies. Surveillance of resistance plasmids is critical to understanding antibiotic resistance transmission. This study analyzed the genome sequences of VREfm isolates collected from the Dallas, TX, area, with particular focus on the mobile elements associated with vancomycin resistance genes. We found that a single plasmid family, the pRUM-like family, was associated with vancomycin resistance in the majority of isolates sampled. Our work suggests that the pRUM-like plasmids should continue to be studied to understand their mechanisms of maintenance, transmission, and evolution in VREfm.

OBJECTIVES: To identify key features of interventions that need to be considered in the design, execution, and reporting of interventions. METHODS: Based on prior work on decomposing psychosocial and clinical interventions, current guidelines for describing interventions, and a review of a broad range of intervention studies, we developed a comprehensive intervention taxonomy. RESULTS: Specific recommendations, rationales, and definitions of intervention delivery and content characteristics including mode, materials, location, schedule, scripting, and sensitivity to participant characteristics, interventionist characteristics, adaptability, implementation, content strategies, and mechanisms of action are provided. CONCLUSIONS: Applying this taxonomy will advance intervention science by (a) improving intervention designs, (b) enhancing replication and follow-up of intervention studies, (c) facilitating systematic exploration of the efficacy and effectiveness of intervention components through cross-study analysis, and (d) informing decisions about the feasibility of implementation in broader community settings. [ABSTRACT FROM AUTHOR]

Silymarin, derived from the milk thistle plant Silybum marianum, is widely used for self-treatment of liver diseases, including hepatitis C virus (HCV), and its antiviral activity has been demonstrated in vitro and in HCV patients administered an intravenous formulation of the major silymarin flavonolignans, silybin A and silybin B. The safety and dose-exposure relationships of higher than customary oral doses of silymarin and its acute effects on serum HCV RNA were evaluated in noncirrhotic HCV patients. Four cohorts of 8 patients with well-compensated, chronic noncirrhotic HCV who failed interferon-based therapy were randomized 3:1 to silymarin or placebo. Oral doses of 140, 280, 560, or 700 mg silymarin were administered every 8 hours for 7 days. Steady-state exposures for silybin A and silybin B increased 11-fold and 38-fold, respectively, with a 5-fold increase in dose, suggesting nonlinear pharmacokinetics. No drug-related adverse events were reported, and no clinically meaningful reductions from baseline serum transaminases or HCV RNA titer were observed. Oral doses of silymarin up to 2.1 g per day were safe and well tolerated. The nonlinear pharmacokinetics of silybin A and silybin B suggests low bioavailability associated with customary doses of silymarin may be overcome with doses above 700 mg. [ABSTRACT FROM AUTHOR]

Cross-sectional and longitudinal analyses were carried out to assess the relationship between dementia patient suffering, caregiver depression, and antidepressant medication use in 1222 dementia patients and their caregivers. We assessed the prevalence of 2 types of patient suffering, emotional and existential distress, and examined their independent associations with caregiver depression and antidepressant medication use when controlling for sociodemographic characteristics of caregivers and patients, cognitive and physical disability of the patient, the frequency of patient memory problems and disruptive behaviors, and the amount of time spent caring for the patient. Multiple linear regression models showed that both aspects of perceived patient suffering independently contribute to caregiver depression (emotional distress: beta=1.24; P<0.001; existential distress: beta=0.66; P<0.01) whereas only existential suffering contributes to antidepressant medication use: odds ratio=1.25 95% confidence interval, 1.10-1.42; P<0.01. In longitudinal analyses, increases in both types of suffering were associated with increases in caregiver depression (emotional distress: beta=1.02; P<0.01; existential distress: beta=0.64; P<0.01). This is the first study to show in a large sample that perceived patient suffering independently contributes to family caregiver depression and medication use. Medical treatment of patients that maintain or improve memory but do not address suffering may have little impact on the caregiver. Alzheimer disease patient suffering should be systematically assessed and treated by clinicians. [ABSTRACT FROM AUTHOR]

Background: Caring for a family member with dementia is extremely stressful, contributes to psychiatric and physical illness among caregivers, and increases the risk for caregiver death. Finding better ways to support family caregivers is a major public health challenge.Objective: To test the effects of a structured multicomponent intervention on quality of life and clinical depression in caregivers and on rates of institutional placement of care recipients in 3 diverse racial or ethnic groups.Design: Randomized, controlled trial.Setting: In-home caregivers in 5 U.S. cities.Participants: 212 Hispanic or Latino, 219 white or Caucasian, and 211 black or African-American caregivers and their care recipients with Alzheimer disease or related disorders.Intervention: Caregivers within each racial or ethnic group were randomly assigned to an intervention or to a control group. The intervention addressed caregiver depression, burden, self-care, and social support and care recipient problem behaviors through 12 in-home and telephone sessions over 6 months. Caregivers in the control group received 2 brief "check-in" telephone calls during the 6-month intervention.Measurements: The primary outcome was a quality-of-life indicator comprising measures of 6-month caregiver depression, burden, self-care, and social support and care recipient problem behaviors. Secondary outcomes were caregiver clinical depression and institutional placement of the care recipient at 6 months.Results: Hispanic or Latino and white or Caucasian caregivers in the intervention group experienced significantly greater improvement in quality of life than those in the control group (P < 0.001 and P = 0.037, respectively). Black or African-American spouse caregivers also improved significantly more (P = 0.003). Prevalence of clinical depression was lower among caregivers in the intervention group (12.6% vs. 22.7%; P = 0.001). There were no statistically significant differences in institutionalization at 6 months.Limitations: The study used only a single 6-month follow-up assessment, combined heterogeneous cultures and ethnicities into a single group, and excluded some ethnic groups.Conclusions: A structured multicomponent intervention adapted to individual risk profiles can increase the quality of life of ethnically diverse dementia caregivers. ClinicalTrials.gov identifier: NCT00177489. [ABSTRACT FROM AUTHOR]

This study used a geographically diverse sample to estimate the total cost of informal care and formal services for community-residing Alzheimer's disease (AD) care recipients. Baseline data were used for 1200 family caregivers from the Resources for Enhancing Alzheimer's Caregiver Health (REACH) study, a multisite intervention trial. The replacement-wage-rate approach estimated informal cost. Formal services were assigned a cost based on secondary sources. Annual cost per care recipient amounted to $23,436 for informal care and $8,064 for formal services. Variation in informal cost was almost entirely due to instrumental activities of daily living (IADLs) assistance. Cross-site differences in cost persisted after controlling for caregiver and care-recipient characteristics. Geographic variation may suggest regional preferences or ethnic/cultural values. Further study is needed to determine whether this reflects differences in access or availability or how including a control group for care recipients with nondementia diagnoses might have affected these findings. [ABSTRACT FROM AUTHOR]

The aim of this study was to assess a newly developed measure for the positive aspects of caregiving using a sample of dementia caregivers. The measure was developed and administered to 1,229 participants in a national collaborative Alzheimer's disease caregiver study and evaluated for validity and reliability using standard psychometric analyses. Factor analysis identified two components in this nine-item measure: Self-Affirmation and Outlook on Life. Cronbach's alphas for the components were .86 and .80, respectively. For the entire scale, Cronbach's alpha was .89. The Positive Aspects of Caregiving measure, tested with a large, diverse, and well-characterized sample shows promise as a valid and reliable instrument. With additional implementation and testing, the measure has the potential to substantially increase our understanding of basic caregiving research and the outcomes of intervention efforts. [ABSTRACT FROM AUTHOR]

Objectives: (1) To estimate caregiver support required by patients 2 months after prolonged (at least 48 h) mechanical ventilation (MV) in an ICU; (2) to describe caregiver burden, caregiver depressive symptomatology, and caregiver limitations in activities; and (3) to investigate factors related to depressive symptoms at 2 months in caregivers.Design: Prospective cohort study.Study Participants: Caregivers of 115 patients who received prolonged MV in an ICU.Measurements: Sociodemographics, employment status, hours spent providing care, help from paid caregiving sources, caregiver burden, and caregiver depressive symptoms.Results: The proportion of patients who survived at least 2 months and required caregiver support was 74.8%. The average age of caregivers was 52.9 years (SD, 14.2), 76.5% were women, and more than half were spouses (52.2%). Only 33 of the caregivers (28.7%) were working, and 30.3% had to reduce their time spent at work to provide care to the patient. The prevalence of risk of clinical depression (defined as Center for Epidemiological Studies depression scale [CES-D] score > or =16) among caregivers was 33.9%. The mean caregiver CES-D score was 13.2 (SD, 11; median, 10). Multiple linear regression analysis showed that higher CES-D score was associated with more hours per day helping with patients' activities of daily living and instrumental activities of daily living (p = 0.003).Conclusions: Two months after being placed on MV for at least 48 h, a high proportion of patients need caregiver support. Approximately 34% of caregivers are at risk of clinical depression. Many caregivers report lifestyle changes and burden when providing care for the patients. [ABSTRACT FROM AUTHOR]

There has been much interest recently in the therapeutic benefits of antioxidants, including a possible protective role in preventing or delaying cognitive decline. This study describes the use of antioxidant supplements among 1,059 rural, noninstitutionalized elderly residents of southwestern Pennsylvania who are participants in the Monongahela Valley Independent Elders Survey. The data were collected during the survey's second wave of follow-up (1989-1991). The mean age of participants was 74.5 years (standard deviation 5.5), and 57.3% were women. Current use of nutritional supplements containing vitamin A, C, or E, beta-carotene, zinc, or selenium was measured through self-report. Subjects were administered a battery of 15 neuropsychological tests measuring performance in several cognitive domains. Of the 1,059 persons, 342 (32.3%) were taking antioxidant supplements. Women and persons with higher levels of education were more often antioxidant users. Antioxidant use did not vary significantly by age, race, or income. In univariate analyses, antioxidant use was significantly and positively associated with performance on several cognitive tests. However, after adjustment for age, education, and sex, there were no significant differences in cognitive test performance between antioxidant users and nonusers. This study is one of only a few that have analyzed the relation between antioxidants and cognition in a community-based sample. After potentially confounding factors are accounted for, the results do not support the hypothesis that antioxidant supplement use is associated with cognitive function. [ABSTRACT FROM AUTHOR]

Background: Although family caregiving has been intensively studied in the past decade, little attention has been paid to the impact of end-of-life care on caregivers who are family members of persons with dementia or to the caregivers' responses to the death of the patient.Methods: Using standardized assessment instruments and structured questions, we assessed the type and intensity of care provided by 217 family caregivers to persons with dementia during the year before the patient's death and assessed the caregivers' responses to the death.Results: Half the caregivers reported spending at least 46 hours per week assisting patients with activities of daily living and instrumental activities of daily living. More than half the caregivers reported that they felt they were "on duty" 24 hours a day, that the patient had frequent pain, and that they had had to end or reduce employment owing to the demands of caregiving. Caregivers exhibited high levels of depressive symptoms while providing care to the relative with dementia, but they showed remarkable resilience after the death. Within three months of the death, caregivers had clinically significant declines in the level of depressive symptoms, and within one year the levels of symptoms were substantially lower than levels reported while they were acting as caregivers. Seventy-two percent of caregivers reported that the death was a relief to them, and more than 90 percent reported belief that it was a relief to the patient.Conclusions: End-of-life care for patients with dementia was extremely demanding of family caregivers. Intervention and support services were needed most before the patient's death. When death was preceded by a protracted and stressful period of caregiving, caregivers reported considerable relief at the death itself. [ABSTRACT FROM AUTHOR]

Objectives: To develop and validate a prediction tool for pediatric acute liver failure (PALF) mortality risks that captures the rapid and heterogeneous clinical course for accurate and updated prediction., Methods: Data included 1144 participants with PALF enrolled during three phases of the PALF registry study over 15 years. Using joint modeling, we built a dynamic prediction tool for mortality by combining longitudinal trajectories of multiple laboratory and clinical variables. The predictive performance for 7-day and 21-day mortality was assessed using the area under curve (AUC) through cross-validation and split-by-time validation., Results: We constructed a prognostic joint model that combines the temporal trajectories of international normalized ratio, total bilirubin, hepatic encephalopathy, platelet count, and serum creatinine. Dynamic prediction using updated information improved predictive performance over static prediction using the information at enrollment (Day 0) only. In cross-validation, AUC increased from 0.784 to 0.887 when measurements obtained between Days 1 and 2 were incorporated. AUC remained similar when we used the earlier subset of the sample for training and the later subset for testing., Conclusions: Serial measurements of five variables in the first few days of PALF capture the dynamic clinical course of the disease and improve risk prediction for mortality. Continuous disease monitoring and updating risk prognosis are beneficial for timely and judicious medical decisions., (© 2023 European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

Modeling disease risk and survival using longitudinal risk factor trajectories is of interest in various clinical scenarios. The capacity to build a prognostic model using the trajectories of multiple longitudinal risk factors, in the presence of potential dependent censoring, would enable more informed, personalized decision making. A dynamic risk score modeling framework is proposed for multiple longitudinal risk factors and survival in the presence of dependent censoring, where both events depend on participants' post-baseline clinical progression and form a competing risks structure. The model requires relatively few random effects regardless of the number of longitudinal risk factors and can therefore accommodate multiple longitudinal risk factors in a parsimonious manner. The proposed method performed satisfactorily in extensive simulation studies. It is further applied to the motivating registry study on pediatric acute liver failure to model death using the trajectories of multiple clinical and biochemical markers. Once established, the model yields an easily calculable longitudinal risk score that can be used for disease monitoring among future patients.

Introduction: We aimed to determine whether the intensity of alanine aminotransferase (ALT) flares during antiviral therapy is associated with the level of hepatitis B surface antigen (HBsAg) decline., Methods: Quantitative HBsAg was determined during tenofovir monotherapy or tenofovir plus peginterferon alfa-2a in 201 participants with hepatitis B e antigen-positive or -negative chronic hepatitis B. A multivariable analysis identified factors associated with a shorter time to reduction in HBsAg., Results: Fifty flares occurred during treatment of which 74% were moderate (ALT >5-10 × upper limit of normal) or severe (ALT >10 × upper limit of normal). These flares were associated with greater HBsAg decline compared with no flares. Significantly faster times to HBsAg decline >1 log 10 IU ( P = 0.04) and to HBsAg level <100 IU/mL ( P = 0.01) were observed with severe flares., Discussions: Flare severity is a potentially important factor associated with shorter time to HBsAg reduction. These findings can be useful when evaluating HBsAg response to evolving hepatitis B virus therapies., (Copyright © 2023 by The American College of Gastroenterology.)

Introduction: Hepatitis B surface antigen (HBsAg) loss is associated with improved long-term outcomes of patients with chronic hepatitis B but is infrequently achieved with current monotherapies. We assessed whether combination strategies that included treatment withdrawal enhanced HBsAg loss., Methods: A randomized (1:1) trial of tenofovir disoproxil fumarate (TDF) for 192 weeks with or without peginterferon (PegIFN) alfa-2a for the first 24 weeks, followed by withdrawal of TDF at week 192 with 48 weeks of off-treatment follow-up to week 240. The primary end point was HBsAg loss at week 240., Results: Of 201 participants (52% HBeAg positive, 12%/6% genotype A/A2, 7% cirrhosis) randomized to TDF + PegIFN (n = 102) or TDF alone (n = 99), 6 participants had lost HBsAg at the end of the treatment phase (week 192), 5 (5.3%) in the combination group, and 1 (1.0%) in the TDF alone group ( P = 0.09). By week 240, 9 participants had cleared HBsAg, 5.3% in combination, and 4.1% in monotherapy arms ( P = 0.73). HBsAg decline and loss occurred earlier with TDF + PegIFN than TDF, with a ≥1-logIU/mL qHBsAg decline by week 24 in 28% in TDF + PegIFN compared with 6% in TDF ( P = 0.04). HBsAg loss occurred in 7 of 12 (58%) with hepatitis B virus subgenotype A2 (all HBeAg positive) compared with only 2 of 189 (1%) with other hepatitis B virus genotypes and in 8 of 93 (8.6%) HBeAg positive vs 1 of 87 (1.1%) HBeAg negative., Discussion: PegIFN combined TDF followed by protocolized TDF withdrawal led to earlier but not higher percentages of HBsAg clearance. Pretreatment HBeAg positivity and subgenotype A2 were strongly associated with HBsAg clearance., (Copyright © 2022 by The American College of Gastroenterology.)

Introduction: Withdrawal of nucleos(t)ide analog therapy is increasingly being evaluated in chronic hepatitis B infection as a strategy to induce hepatitis B surface antigen (HBsAg) loss. The Hepatitis B Research Network Immune-Active Trial evaluated treatment with tenofovir (TDF) for 4 years ± an initial 6 months of peginterferon-α (PegIFN) (NCT01369212) after which treatment was withdrawn., Methods: Eligible participants (hepatitis B e antigen [HBeAg]-/anti-HBe+, hepatitis B virus [HBV] DNA <10 3 IU/mL, no cirrhosis) who discontinued TDF were followed for at least 1 year with optional follow-up thereafter. Retreatment was based on predefined criteria., Results: Among 201 participants who received 4 years of treatment, 97 participants (45 TDF and 52 TDF + PegIFN arm, 79 Asian) discontinued TDF. HBsAg loss occurred in 5 participants, 2 within 25 weeks and 3 within 89-119 weeks postwithdrawal (cumulative rate 4.3% by 2 years). Alanine aminotransferase (ALT) flares (>5× upper limit of normal) after TDF withdrawal occurred in 36 (37.1%) participants and occurred more frequently and earlier in those HBeAg- compared with HBeAg+ at treatment initiation. ALT flares were associated with older age and higher HBV DNA pretreatment and at the visit before the flare. ALT flares were not significantly associated with HBsAg decline or loss but were associated with immune active disease at 1 year (70.6% vs 11.9%, P < 0.0001) and 2 years (66.7% vs 25.9%, P = 0.03) postwithdrawal. Treatment reinitiation was required in 13 (13.4%) participants, and 13 others remained in a sustained inactive carrier state by the end of the study follow-up. No criteria reliably predicted safe treatment withdrawal., Discussion: Results from this trial do not support TDF withdrawal as a therapeutic strategy. HBsAg loss was infrequent within 2 years of stopping long-term TDF. If withdrawal is considered, HBV DNA should be carefully monitored with reinitiation of therapy if levels rise above 4 log 10 IU/mL to reduce the risk of ALT flares, as they were not associated with subsequent HBsAg decline or loss., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The American College of Gastroenterology.)

Background: Prospective data regarding the safety and yield of liver biopsy in both adults and children with chronic hepatitis B are limited. The aim of this study is to report safety, yield, and complication rates among adults and children with chronic hepatitis B undergoing percutaneous liver biopsy., Methods: Data on the indication for procedural characteristics and complication rate for liver biopsies performed as part of the Hepatitis B Research Network were prospectively recorded on a study case report form and analyzed in aggregate., Results: Among 2506 adult and pediatric subjects enrolled in the Hepatitis B Research Network between 2011 and 2018, 465 (19%) underwent 491 liver biopsies for clinical or research reasons. Adequate liver tissue was obtained in 98% of the procedures. In total, there were 32 complications reported for 24 biopsies: 23 biopsies with 30 complications in adults and 1 biopsy with 2 complications in children. Pain (n=19) and vasovagal reaction (n=6) were the most common complications. There were 7 serious adverse events, including an arterioportal venous fistula, a pneumothorax, 4 cases of bleeding, and severe pain with no associated condition. There were no deaths., Conclusions: These data demonstrate that percutaneous liver biopsy is associated with a high yield of tissue (98%) and a rate of serious complications of 1.4% in both children and adults with chronic HBV. These results support the focused use of liver biopsy in the evaluation of novel treatments in development for chronic hepatitis B., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.)

Importance: Disparities in treatment initiation may affect outcomes, but data on racially diverse populations with chronic hepatitis B virus (HBV) infection are limited., Objective: To examine whether HBV treatment initiation and outcomes differ among racial groups., Design, Setting, and Participants: From January 14, 2011, to January 28, 2018, hepatitis B surface antigen-positive adults (age ≥18 years) not receiving anti-HBV therapy were enrolled and followed up at weeks 12, 24, and every 24 weeks thereafter in a multicenter longitudinal cohort study (Hepatitis B Research Network [HBRN] adult cohort study) conducted in North America. The last study visit and data collection were completed January 28, 2019. Data were analyzed from August 27, 2021, to August 25, 2022. All HBRN participants were included unless they had acute HBV, HIV, hepatitis C or D, less than 24-weeks of follow-up after enrollment, initiated treatment at or immediately after enrollment, or had unknown race., Exposures: Participants had clinical and laboratory assessments and could receive anti-HBV treatment after enrollment., Main Outcomes and Measures: Hepatitis B virus treatment initiation and major adverse liver outcomes (hepatic decompensation, hepatocellular carcinoma, liver transplant, and death)., Results: Of 1550 participants, 193 (12%) were African American or Black, 1157 (75%) were Asian, 157 (10%) were White, and 43 (3%) were other races; 789 (51%) were women, and the median age was 41.2 (IQR, 32.9-51.6) years. Sociodemographic and virologic parameters differed between groups. During 5727 person-years of follow-up, 504 participants initiated treatment, with incidences of 4.8 per 100 person-years in African American or Black individuals, 9.9 per 100 person-years in Asian individuals, 6.6 per 100 person-years in White individuals, and 7.9 per 100 person-years in those of other races (P < .001). A lower proportion (14%) of African American or Black participants met treatment criteria compared with Asian (22%) and White (27%) individuals (P = .01). The cumulative probabilities of treatment initiation after meeting the criteria were not significantly different among racial groups (African American or Black, 0.45; Asian, 0.38; White, 0.40 at 48 weeks and African American or Black, 0.45; Asian, 0.51; White, 0.51 at 72 weeks; P = .68). The incidence of major adverse liver outcomes was 0.1 per 100 person-years and did not differ by race., Conclusions and Relevance: In this observational study of chronic HBV, African American or Black participants were less likely than individuals of other races to meet treatment criteria, but among those who did, HBV treatment receipt did not differ significantly by race or socioeconomic factors. Not all eligible participants initiated treatment, but adverse liver outcomes were rare. These findings may not be generalizable to patients with chronic HBV receiving care in other settings.

Objective: To examine associations of objectively-measured free-living physical activity (PA) with changes in depressive symptoms and mental and physical health-related quality of life (HRQoL) over 7 years after Roux-en-Y gastric bypass surgery (RYGB)., Background: The contributions of PA to improvements in mental and physical health after RYGB, independent of weight loss, are unclear., Methods: Adults undergoing RYGB in a US multi-center cohort study wore an activity monitor and completed the Beck depression inventory (BDI) and 36-Item Short Form Health Survey (SF-36) annually ≤7 years (N = 646; 78% female, median age 47 years, median body mass index 46kg/m 2 ). Linear mixed models estimated associations of quartiles of steps, sedentary behavior (SB), and moderate-to-vigorous intensity physical activity (MVPA), respectively, with pre-to-post-surgery changes in the BDI and SF-36 mental component summary and physical component summary scores, respectively, over 1-7 years post-surgery, with adjustment for sex, age, race, pre-surgerybody mass index, the respective pre-surgery score, treatment for depression (time-varying) and pre-to-post-surgery weight change (time-varying)., Results: There were dose-response associations between steps, SB (inverse) and MVPA quartiles, respectively, with improvements in each score. Across follow-up, mean improvements in the BDI, Mental Component Summary and physical component summary scores, were 1.9 [95% confidence interval (CI), 1.0-2.8], 3.1 (95% CI, 1.5-4.7), and 4.0 (95% CI, 2.7-5.4) points higher, respectively, in the highest versus lowest steps quartile., Conclusion: Among adults who underwent RYGB, multiple objective PA measures were associated with decreases in depressive symptoms and improvements in mental and physical HRQoL throughout 7 years, independent of weight loss, indicating PA is a modifiable behavior to augment outcomes., Competing Interests: All authors will complete the ICMJE form for disclosure of potential conflicts of interest. Authors have no support from any organization for the submitted work; no financial relationships with any organizations that might have an interest in the submitted work in the previous 3 years; and no other relationships or activities that could appear to have influenced the submitted work other than the following: Dr. King reports grants from Abbott pharmaceuticals outside of the submitted work. Dr. Courcoulas reports grants from Covidien/Ethicon and Allurion outside of the submitted work. Dr. White, Ms. Hinerman, and Dr. Belle have nothing to disclose., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

In medical studies, some therapeutic decisions could lead to dependent censoring for the survival outcome of interest. This is exemplified by a study of paediatric acute liver failure, where death was subject to dependent censoring due to liver transplantation. Existing methods for assessing the predictive performance of biomarkers often pose the independent censoring assumption and are thus not applicable. In this work, we propose to tackle the dependence between the failure event and dependent censoring event using auxiliary information in multiple longitudinal risk factors. We propose estimators of sensitivity, specificity and area under curve, to discern the predictive power of biomarkers for the failure event by removing the disturbance of dependent censoring. Point estimation and inferential procedures were developed by adopting the joint modelling framework. The proposed methods performed satisfactorily in extensive simulation studies. We applied them to examine the predictive value of various biomarkers and risk scores for mortality in the motivating example.

Objective: To examine associations of objectively-measured physical activity (PA) with changes in weight after roux-en-Y gastric bypass (RYGB) over 7 years., Background: The contribution of free-living PA to surgery-induced weight loss and subsequent weight regain is not well understood., Methods: Participants of a multi-center prospective cohort study of bariatric surgery were followed annually ≥7 years. Of 807 participants who underwent RYGB and were given an activity monitor, 649 (80%) had sufficient data for this report (78% female; median age 47 years; median body mass index 46 kg/m2). Mean daily steps, hours/day in SB and minutes/week in moderate-to-vigorous physical activity (MVPA) were determined at each assessment. Mixed models tested associations between PA measures and weight outcomes, controlling for sociodemographics, health status, and eating behaviors., Results: Across follow-up, mean pre to postsurgery changes in PA were small, and mean postsurgery PA level was below PA recommendations for health (eg, 101 MVPA min/week 7 years postsurgery versus the ≥150 MVPA min/week recommendation). There was a dose-response association between more steps, less SB and more MVPA with greater weight loss. Steps and SB, but not MVPA, were also associated with weight regain. For example, participants in the highest versus lowest steps quartile lost 2.9% (95% confidence interval, 1.8-4.1) more of their presurgery weight and regained 5.4% (95% confidence interval, 2.4-8.3) less of their maximum weight lost across follow-up., Conclusions: Despite only small increases in objectively-measured PA level after RYGB, PA level was independently associated with weight outcomes of bariatric surgery throughout 7 years of follow-up., Reprints: Reprints will not be available from the authors., Competing Interests: All authors will complete the ICMJE Form for Disclosure of Potential Conflicts of Interest. Authors have no support from any organization for the submitted work; no financial relationships with any organizations that might have an interest in the submitted work in the previous 3 years; and no other relationships or activities that could seem to have influenced the submitted work other than the following: Dr. King reports grants from Abbott pharmaceuticals outside of the submitted work. Dr. Courcoulas reports grants from Covidien/Ethicon and Allurion outside of the submitted work. Dr. Belle. Dr. White, Ms. Hinerman and Mr. Saad have nothing to disclose., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: To evaluate smoking history and change in smoking behavior, from 1 year before through 7 years after Roux-en-Y gastric bypass (RYGB) surgery, and to identify risk factors for post-surgery smoking., Background: Smoking behavior in the context of bariatric surgery is poorly described., Methods: Adults undergoing RYGB surgery entered a prospective cohort study between 2006 and 2009 and were followed up to 7 years until ≤2015. Participants (N = 1770; 80% female, median age 45 years, median body mass index 47 kg/m2) self-reported smoking history pre-surgery, and current smoking behavior annually., Results: Almost half of participants (45.2%) reported a pre-surgery history of smoking. Modeled prevalence of current smoking decreased in the year before surgery from 13.7% [95% confidence interval (CI) = 12.1-15.4] to 2.2% (95% CI = 1.5-2.9) at surgery, then increased to 9.6% (95% CI = 8.1-11.2) 1-year post-surgery and continued to increase to 14.0% (95% CI = 11.8-16.0) 7-years post-surgery. Among smokers, mean packs/day was 0.60 (95% CI = 0.44-0.77) at surgery, 0.70 (95% CI = 0.62-0.78) 1-year post-surgery and 0.77 (95% CI = 0.68-0.88) 7-years post-surgery. At 7-years, smoking was reported by 61.7% (95% CI = 51.9-70.8) of participants who smoked 1-year pre-surgery (n = 221), 12.3% (95% CI = 8.5-15.7) of participants who formerly smoked but quit >1 year pre-surgery (n = 507), and 3.8% (95% CI = 2.1-4.9) of participants who reported no smoking history (n = 887). Along with smoking history (ie, less time since smoked), younger age, household income <$25,000, being married or living as married, and illicit drug use were independently associated with increased risk of post-surgery smoking., Conclusion: Although most adults who smoked 1-year before RYGB quit pre-surgery, smoking prevalence rebounded across 7-years, primarily due to relapse., Competing Interests: All authors will complete the ICMJE form for disclosure of potential conflicts of interest. Authors have no support from any organization for the submitted work; no financial relationships with any organizations that might have an interest in the submitted work in the previous 3 years; and no other relationships or activities that could seem to have influenced the submitted work other than the following: Dr. Ahmed reports grants from Allurion Technologies Inc. outside the submitted work. Dr. Courcoulas reports grants from Covidien/Ethicon and Allurion Technologies outside of the submitted work. Dr. Pomp received speaker honoraria from WL Gore & Associates and Medtronic outside of the submitted work. Dr. Pories reports grant support from Johnson & Johnson and Nestle Corp., all funds go directly to the University for Research. Dr. Yanovski reports spousal research project support to his institution from Rhythm Pharmaceuticals. Drs. Belle, King, White, and Wolfe have nothing to disclose., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Children infected with SARS-CoV-2 are often asymptomatic or have only mild symptoms, leading to underestimation of disease prevalence in symptom-based testing strategies., Objectives: This study sought to determine pediatric SARS-CoV-2 disease burden during local mitigation efforts by using antibody testing to compare seroprevalence estimates to cumulative PCR prevalence estimates., Study Design: In this cross-sectional study, we collected 1142 strict phase and 1196 relaxed phase remnant blood specimens from patients less than 19-years-old in southwestern Pennsylvania (SWPA). Patients were excluded if their residential zip code was outside the region of interest, if they were under 6-months-old, or they had recently received antibody-modifying treatments. Demographic, encounter, and laboratory electronic medical record information was extracted. Samples were tested for SARS-CoV-2 spike protein IgG using an EUA ELISA, and PCR results were recorded from county health department data. Seroprevalence and Clopper-Pearson exact 95% confidence intervals were calculated., Results: The observed seroprevalence of SARS-CoV-2 spike protein antibodies in children during strictest mitigation was 0.53% (95% CI 0.19, 1.14) and 0.92% (95% CI 0.46,1.64) during moderately relaxed. Strict and relaxed phase PCR-based prevalence were significantly higher, 2.87% (95% CI 1.95, 4.08) and 3.64 (95% CI 3.01, 4.38), respectively., Conclusions: Estimates of pediatric seroprevalence were significantly lower than cumulative PCR prevalence estimates, and less than adult seroprevalence estimates, potentially due to biological, population, or sampling differences. Biological differences in pediatric immune responses to SARS-CoV-2 may make serosurvey interpretation challenging and these differences warrant further study., Competing Interests: None of the authors have any conflicts of interest that relate to the work conducted for this manuscript., (© 2021 The Authors. Published by Elsevier Ltd.)

Background and Aims: Outcomes of persons with chronic hepatitis B virus (HBV) infection in the era of antiviral therapy (AVT) are not well characterized. We determined the incidence and factors associated with clinical outcomes in a multiethnic, North American cohort of adults with chronic HBV infection, who were not on AVT at enrollment., Approach and Results: Adults with chronic HBV infection, not receiving AVT, and without a history of decompensation, HCC, or liver transplantation (LT), were prospectively followed. Participants with known human immunodeficiency virus (HIV), hepatitis C virus, or hepatitis D virus (HDV) coinfection were excluded. During follow-up, treatment could be initiated per standard of care. Clinical outcomes included: incident cirrhosis, decompensation, HCC, OLT, and HBV-related death. Among 1,418 participants analyzed, 51.5% were women, median age was 41.1 years, 75% were Asian, 10% White, 13% Black, 24% HBeAg(+), and 1.5% cirrhosis at baseline. During the study, 274 started treatment, 83 had an alanine aminotransferase flare, 118 of 330 initially HBeAg(+) became HBeAg(-), and 90 of 1,329 became HBsAg(-). After 6,641 person-years follow-up, 8 participants (4 of 21 with baseline cirrhosis) had 12 clinical outcomes (2 decompensation, 5 HCC, 2 OLT, and 3 HBV-related deaths) and 19 of 1,397 had incident cirrhosis. Twenty-one of 26 participants had first outcome before treatment, none had become HBsAg(-), whereas 5/9 HBeAg(+) had become HBeAg(-) at time of first outcome. Cumulative percentage of clinical outcomes was 16% at year 4 in participants with baseline cirrhosis and 2% (including incident cirrhosis) at year 7 in those without., Conclusions: Incidence of adverse outcomes was low in this closely monitored, large cohort of North American adults with predominantly inactive, chronic HBV without cirrhosis. Our data highlight the benefits of HBsAg loss and the importance of early diagnosis and treatment to prevent cirrhosis and other complications of chronic HBV infection., (© 2020 by the American Association for the Study of Liver Diseases.)

Objective: To identify patient behaviors and characteristics related to weight regain after Roux-en-Y gastric bypass surgery (RYGB)., Background: There is considerable variation in the magnitude of weight regain after RYGB, highlighting the importance of patient-level factors., Methods: A prospective cohort study of adults who underwent bariatric surgery in 6 US cities between 2006 and 2009 included presurgery, and 6-month and annual assessments for up to 7 years. Of 1573 eligible participants, 1278 (81%) with adequate follow-up were included (80% female, median age 46 years, median body mass index 46 kg/m). Percentage of maximum weight lost was calculated each year after weight nadir., Results: Weight was measured a median of 8 (25th-75th percentile, 7-8) times over a median of 6.6 (25th-75th percentile, 5.9-7.0) years. β coefficients, that is, the mean weight regain, compared with the reference, and 95% confidence interval, are reported. Postsurgery behaviors independently associated with weight regain were: sedentary time [2.9% (1.2-4.7), for highest vs lowest quartile], eating fast food [0.5% (0.2-0.7) per meal/wk], eating when feeling full [2.9% (1.2-4.5)], eating continuously [1.6% (0.1-3.1)], binge eating and loss-of-control eating [8.0% (5.1-11.0) for binge eating; 1.6 (-0.1 to 3.3) for loss of control, vs neither], and weighing oneself

Introduction and Objectives: Universal vaccination at birth and in infancy is key to the elimination of chronic hepatitis B infection. We aimed to assess hepatitis B immune-prophylaxis and perinatal transmission knowledge, in a large and ethnically diverse cohort of previously pregnant North American women, chronically infected with hepatitis B., Materials and Methods: The Hepatitis B Research Network (HBRN) is comprised of 28 Clinical Centers in the United States and Canada. Female cohort participants were administered a questionnaire to assess: (1) their assertion of knowledge regarding HBV prophylaxis at birth, testing, and diagnosis of hepatitis B in their children, and (2) the percentage of affirmative to negative responses for each of the HBV-related interventions her child may have received. The relationship between asserted knowledge, actions taken and maternal demographics were assessed., Results: A total of 351 mothers with 627 children born in or after 1992 were included. Median age at enrollment was 39.8 years. Mothers were mostly foreign-born with the largest percentage from Asia (73.4%) and Africa (11.7%). Of the 627 children, 94.5% had mothers who asserted that they knew whether their child had received HBIG or HBV vaccine at birth, for 88.8% of the children, their mothers indicated that they knew if their child was tested for HBV and for 84.5% of children, their mothers knew if the child was diagnosed with HBV infection. Among children whose mothers asserted knowledge of their HBV management, 95.3% were reported to have received HBIG or HBV vaccine, 83.4% of children were said to have been tested for HBV, and 4.8% of children were said to have been diagnosed with HBV. Younger maternal age was the only factor significantly associated with higher percentage of children for whom mothers reported knowledge of testing (p=0.02) or diagnosis of HBV (p=0.02)., Conclusions: While high percentages of North American children had mothers asserting knowledge of HBV prophylaxis and testing, knowledge gaps remain, with mothers of 5.5-15.5% of children lacking knowledge of key components of the HBV prevention and diagnosis in the perinatal setting. Targeted education of HBsAg-positive mothers may aid in closing this gap and reducing vertical transmission., (Copyright © 2020 Fundación Clínica Médica Sur, A.C. Published by Elsevier España, S.L.U. All rights reserved.)

Background & Aims: The incidence and outcomes of alanine aminotransferase (ALT) flares during the natural history of chronic HBV infection has not been determined in a large, racially heterogeneous group of patients in North America., Methods: We collected data from the Hepatitis B Research Network-an observational cohort study of untreated adults with chronic HBV infection enrolled at 21 sites in the United States and Canada. Clinical and laboratory data were collected from 1587 participants (49.9% male, 73.7% Asian, 35.2% genotype B infection, mean age of 42.6 years) at enrollment, at weeks 12 and 24, and every 24 weeks thereafter for a planned 5 years of follow up (from January 2011 through May 2016). Participants were excluded if they had a history of hepatic decompensation, hepatocellular carcinoma, solid organ or bone marrow transplantation, chronic immune suppression, or antiviral therapy within 6 months before enrollment. Levels of ALT were measured in serum samples and flares were defined as at least 10 times the upper limit of normal (300 U/L in males and 200 U/L in females)., Results: ALT flares occurred in 102 participants (6%), with 31 flares (30%) occurring at baseline. The 4-year cumulative incidence of ALT flares was 5.7%. The median peak level of ALT was 450 U/L (25th-75th percentile, 330 U/L to 747 U/L) with a maximum of 2578 U/L. In multivariable analysis, factors associated with the occurrence of an ALT flares were: male sex (odds ratio [OR], 3.02; P=.0007), higher baseline HBV DNA values (OR per log10, 1.41; P<.0001), at risk alcohol use (OR, 2.27 vs none or moderate; P=.02), and higher FIB-4 values (OR, 1.85 per log2; P<.0001). Older age was associated with lower odds of an ALT flare (OR, 0.63 per 10 years; P=.004). Rate of decrease in level of HBV DNA by 1 log10 or more (59 vs 23 per 100 person-years for HB e antigen (HBeAg)-positive vs HBeAg-negative patients; P=.003) and HBeAg loss (47 vs 15 per 100 person-years; P=.002) were higher in patients with an ALT flare than in patients without, but the rate of HBsAg loss was similar (4 vs 2 per 100 person-years; P=.26). No hepatic decompensation, liver transplants, or deaths were observed in participants with ALT flares., Conclusion: In a large racially heterogeneous cohort of adults with chronic HBV infection, the cumulative incidence of severe ALT flares was low and associated with greater decreases in HBV DNA and loss of HBeAg, but not with loss of HBsAg., (Copyright © 2019 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: Patients having bariatric surgery have lower mortality compared with those with similar body mass index who do not undergo surgery. It is unclear whether mortality post-bariatric surgery is similar to the general population. The benefit of bariatric surgery would be highlighted should people previously at high risk for premature death have comparable, or better, mortality as the general population., Objective: To compare mortality after bariatric surgery to the general U.S. population of the same age, sex, and race., Setting: The Longitudinal Assessment of Bariatric Surgery-2 (LABS-2) prospective cohort of 2458 adults who underwent bariatric surgery at 10 U.S. hospitals between 2006 and 2009., Methods: Deaths were identified via LABS-2 follow-up and the National Death Index. Standardized mortality ratios (SMR) of post-bariatric surgery mortality observed in LABS-2 versus age-, sex-, race-, and year-adjusted expected mortality in the general U.S. population were calculated and compared with 1, which results when the number of observed and expected deaths are equal., Results: LABS-2 median follow-up was 6.6 (interquartile range: 5.9-7.0) years postsurgery. Seventy-six deaths were observed over 15,616 person-years (PY) of observation (4.9 deaths/1000 PY). The rate expected in the general U.S. population with the same age, sex, race, and year distribution was 4.8 deaths per 1000 PY (SMR = 1.02, 95% confidence interval [CI]: .80-1.27). There were no significant differences between observed and expected mortality by surgical procedure. Compared with expected mortality in the general U.S. population, people 35-44 years old at time of surgery had significantly more deaths (SMR = 2.06, 95% CI: 1.22-3.25), while people at least 55 years of age had significantly fewer (SMR = .63, 95% CI: .42-.92). Significantly more deaths than expected occurred in the perioperative period and 5-7 years after surgery., Conclusions: Mortality within 7 years of bariatric surgery is comparable to the general U.S. population, which is likely to have better survival than people with severe obesity. However, more deaths than expected were identified 5-7 years after surgery., (Copyright © 2019 American Society for Bariatric Surgery. Published by Elsevier Inc. All rights reserved.)

Background: Some studies suggest that changes in weight or metabolic outcomes are affected by the lengths of the gastrointestinal limbs in the Roux-en-Y gastric bypass., Methods: Participants (N = 1,770) underwent primary Roux-en-Y gastric bypass and were followed ≤7 years in the Longitudinal Assessment of Bariatric Surgery-2, a multicenter US cohort study. Alimentary limb and biliopancreatic limb lengths were measured according to research protocol; common channel was measured in a subsample (N = 547). Aimentary limb, biliopancreatic limb, and common channel ratio to total small bowel length were calculated., Results: Median presurgery body mass index was 46 (25th-75th percentile: 43-51) kg/m 2 . Medians (25th-75th percentiles) for alimentary limb length were 125 cm (100-150), for biliopancreatic limb length were 50 cm (50-60), and common channel length were 410 cm (322-520). Statistics for ratios to the small bowel length were 0.23 (0.18-0.27) for alimentary limb, 0.09 (0.07-0.10) for biliopancreatic limb, and 0.69 (0.63-0.73) for common length. There were no significant associations between alimentary limb, biliopancreatic limb, common channel, alimentary limb ratio, biliopancreatic limb ratio or common channel ratio, and either weight loss or improvement in cardiometabolic outcomes., Conclusion: The common channel length in Roux-en-Y gastric bypass is highly variable between individuals. None of the limb lengths in this study, nor alimentary limb, biliopancreatic limb, or common channel ratios, seem to be related to weight loss or metabolic improvements >7 years., (Copyright © 2019 Elsevier Inc. All rights reserved.)

The botanical product silymarin, an extract of milk thistle, is commonly used by patients to treat chronic liver disease and may be a treatment for NASH due to its antioxidant properties. We aimed to assess the safety and efficacy of higher than customary doses of silymarin in non-cirrhotic patients with NASH. This exploratory randomized double-blind placebo controlled multicenter Phase II trial tested a proprietary standardized silymarin preparation (Legalon®, Rottapharm|Madaus, Mylan) and was conducted at 5 medical centers in the United States. Eligible adult patients had liver biopsy within 12 months showing NASH without cirrhosis with NAFLD Activity Score (NAS) ≥4 per site pathologist's assessment. Participants were randomized to Legalon® 420 mg, 700 mg, or placebo t.i.d. for 48 weeks. The primary endpoint was histological improvement ≥2 points in NAS. Of 116 patients screened, 78 were randomized. There were no significant differences in adverse events among the treatment groups. After 48-50 weeks, 4/27 (15%) in the 700 mg dose, 5/26 (19%) participants randomized to 420 mg, and 3/25 (12%) of placebo recipients reached the primary endpoint (p = 0.79) among all randomized participants, indicating no benefit from silymarin in the intention to treat analysis Review by a central pathologist demonstrated that a substantial number of participants (49, 63%) did not meet histological entry criteria and that fibrosis stage improved most in the placebo treated group, although not significantly different from other groups. Silymarin (Legalon®) at the higher than customary doses tested in this study is safe and well tolerated. The effect of silymarin in patients with NASH remains inconclusive due to the substantial number of patients who entered the study but did not meet entry histological criteria, the lack of a statistically significant improvement in NAS of silymarin treated patients, and the unanticipated effect of placebo on fibrosis indicate the need for additional clinical trials. Trial Registration: clinicaltrials.gov, Identifier: NCT00680407., Competing Interests: The authors confirm the following competing interests: Victor Navarro, M.D. No conflicts relevant to this trial; Steven H. Belle, Ph.D. No conflicts relevant to this trial; Massimo D’Amato, M.D. Dr. D’Amato was an employee of the Italian subsidiary of the Rottapharm|Madaus, now Mylan, manufacturer of the silymarin formulation used in the study, at the time of the study, but left Rottapharm|Madaus to join Rottapharm Biotech in 2014 and participated in the preparation of the manuscript as an independent scientist. Rottapharm Biotech is an independent company from Mylan, does not market Legalon nor any sylimarin formulation and as corporate entity had no role in the conception, design and performance of this study, nor in the decision to submit the manuscript for publication; Nezam Afdhal, M.D. Dr. Afdhal serves as a consultant/advisory board member for Merck, Gilead, Echosens, Ligand, Jannsen, and Shionogi. He is Director, TRIO Heathcare. He owns stock or stock options in Sprinbank, Allurion, and TRIO; Elizabeth M. Brunt, M.D. Dr. Brunt was compensated by Rottapharm|Madaus for her review of the liver biopsies; Michael W. Fried, M.D. Dr. Fried receives research grants paid to his institution from AbbVie, BMS, Gilead, Merck. He serves as an unpaid consultant to AbbVie, BMS, Merck, and TARGET PharmaSolutions and owns stock in TARGET PharmaSolutions, which is held in an independently managed trust; K. Rajender Reddy, M.D. Dr. Reddy serves on the Scientific Advisory Board-Gilead, Merck, Abbvie, BMS, Spark Therapeutics. Research Support (Paid to the University of Pennsylvania)-Gilead, Merck, Abbvie, BMS, Conatus, Mallinckrodt, Intercept, Exact Sciences. DSMB-Novartis; Abdus S. Wahed, PhD: No conflicts relevant to this trial; Stephen Harrison, M.D. Consultant/Advisory board for Prometic, Innovate, Gelesis, CiVi, Contravir, Cymabay, Galectin, Northsea, Hightide, Madrigal, Metacrine, NGM, Cirius, Akero, Terns, Viking, Blade, Poxel, 3v Bio, Axcella, Merck, Gilead, Intercept, Genfit, Novo Nordisk, Echosens, Perspectum, Novartis and Medpace. Research support from Gilead, Novo Nordisk, BMS, Pfizer, Novartis, Cymabay, NGM, Axcella, Hightide, Conatus, Galectin, Intercept, Genfit, Akero, Metacrine, Cirius, Contravir, Madrigal, Enyo, Northsea. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Introduction: Alterations in the immune system can result in alanine aminotransferase (ALT) flares either during pregnancy or after delivery in women with chronic hepatitis B virus (HBV) infection. The aim of this study was to prospectively assess changes in serum biochemical and virological markers of HBV infection during and after pregnancy in a large North American cohort of pregnant women with chronic HBV., Methods: Adult pregnant women enrolled in the Hepatitis B Research Network between 2011 and 2016 were included. Serum ALT values and HBV DNA viral levels were obtained at <28 weeks and >28 weeks of gestation and <16 weeks, 16-31 weeks, and 32-48 weeks postpartum. Outcomes of ALT flares included severity, duration, and initiation of antiviral therapy., Results: Among the 158 pregnant women with chronic HBV, the median age was 33 years, 73% were Asian, and 63% were hepatitis B e antigen (HBeAg) negative. The median HBV DNA level was substantially higher in the HBeAg-positive vs HBeAg-negative women (1.3 × 10 vs 343 IU/mL), but serum ALT levels at their first study visit were similar. Among untreated pregnant women, there was a very mild increase in serum ALT postpartum among both HBeAg-positive and HBeAg-negative women (P < 0.001). Serum ALT flares (range 107-513 U/L) developed in 3.4% (5/149) during pregnancy and in 4.3% (4/92) after delivery. Twenty-two percent were initiated on antiviral therapy. After withdrawal of prophylactic anti-HBV therapy, 17.2% (5/29) developed serum ALT flares (range 107-208 U/L) within 14 weeks of drug discontinuation, and 3 additional women had flares despite continuous anti-HBV therapy during pregnancy or postpartum. Many ALT flares were not associated with significant changes in HBV DNA levels. No flares were severe with elevations of bilirubin or clinical decompensation., Discussion: Spontaneous ALT flares in untreated pregnant women with chronic HBV are infrequent, mild, and self-limited both prepartum and postpartum. Although flares after the withdrawal of antiviral therapy postpartum are more common, they were also mild and self-limited. Further studies of the immunopathogenesis of pregnancy-related flares are needed, as well as effects on long-term outcome of the mother and infant.

Hepatitis B e antigen (HBeAg) is an important serological marker of hepatitis B virus (HBV) infection and is associated with higher levels of viraemia, increased risk of infectivity to others and increased risk of hepatocellular carcinoma. We analysed HBeAg status in a large cohort of adults and children enrolled in Cohort Studies of the Hepatitis B Research Network, long-term natural history studies of chronic HBV infection. A cross-sectional analysis examined factors associated with HBeAg positivity, including demographic and virologic data, across the age spectrum. Among 2241 enrolled participants who met criteria for this analysis, 825 (37%) were seropositive for HBeAg. The prevalence of HBeAg was lower in those with older age, ranging from 85% among those up to 10 years of age to only 12% among those older than 50 years. In addition to age, both race and HBV genotype were independently associated with HBeAg positivity. There was a significant interaction between age and race; the prevalence of HBeAg was significantly higher among Asians > 10-30 years old vs Whites or Blacks who were >10 to 30 years old and those infected with HBV genotype C. Conversely, the presence of the basal core promoter and precore variants was associated with significantly lower prevalence of HBeAg, even when adjusted for age, race and genotype. These data will provide a better understanding of factors associated with seropositivity for HBeAg and may lead to better strategies for preventing HBV infection and broader indications for antiviral therapy., (© 2019 John Wiley & Sons Ltd.)

Background: Pediatric acute liver failure (PALF) is a public heath burden, often requiring prolonged hospitalization and liver transplantation. Hepatic encephalopathy (HE) is a complication of PALF with limited diagnostic tools to predict outcomes. Serum neurological markers (neuron-specific enolase, S100β, and myelin basic protein) can be elevated in traumatic or ischemic brain injury. We hypothesized that these neuromarkers would be associated with the development of HE in PALF., Methods: PALF study participants enrolled between May 2012 and December 2014 by 12 participating centers were the subjects of this analysis. Daily HE assessments were determined by study investigators. Neurological and inflammatory markers were measured using enzyme-linked immunosorbent assay and MILLIPLEX techniques, respectively. To model encephalopathy, these markers were log2 transformed and individually examined for association with HE using a generalized linear mixed model with a logit link and random intercept., Results: Eighty-two children had neurological and inflammatory marker levels and HE assessments recorded, with the majority having assessments for 3 days during their illness. An indeterminate diagnosis (29%) was most common and the median age was 2.9 years. Significant associations were observed for HE with S100β (odds ratio 1.16, 95% confidence interval [1.03-1.29], P = 0.04) and IL-6 (odds ratio 1.24 [1.11-1.38], P = 0.006)., Conclusions: Serum S100β and IL-6 are associated with HE in children with PALF. Measuring these markers may assist in assessing neurological injury in PALF, impacting clinical decisions.

Objective: The goal of the present study was to deconstruct the 17 treatment arms used in the Early Adult Reduction of weight through LifestYle (EARLY) weight management trials., Methods: Intervention materials were coded to reflect behavioral domains and behavior change techniques (BCTs) within those domains planned for each treatment arm. The analytical hierarchy process was employed to determine an emphasis profile of domains in each intervention., Results: The intervention arms used BCTs from all of the 16 domains, with an average of 29.3 BCTs per intervention arm. All 12 of the interventions included BCTs from the six domains of Goals and Planning, Feedback and Monitoring, Social Support, Shaping Knowledge, Natural Consequences, and Comparison of Outcomes; 11 of the 12 interventions shared 15 BCTs in common across those six domains., Conclusions: Weight management interventions are complex. The shared set of BCTs used in the EARLY trials may represent a core intervention that could be studied to determine the required emphases of BCTs and whether additional BCTs add to or detract from efficacy. Deconstructing interventions will aid in reproducibility and understanding of active ingredients., (© 2019 The Obesity Society.)

Monotherapy with interferon or nucleoside analog is generally not recommended during the immune-tolerant (IT) phase of chronic hepatitis B virus (HBV) infection. Recognition that high HBV DNA levels are associated with hepatocellular carcinoma has increased interest in treating HBV in the IT phase. Small pediatric studies reported efficacy with combination nucleoside analog and interferon therapy. The aim of this study was to evaluate the safety and efficacy of the combination of entecavir and peginterferon in adults in the IT phase of chronic HBV infection. Hepatitis B e antigen (HBeAg)-positive adults with HBV DNA > 10 7 IU/mL and alanine aminotransferase (ALT) ≤ 1.5 times the upper limit of normal (ULN) (male: ≤ 45, female: ≤ 30 U/L) received entecavir 0.5 mg daily for 8 weeks followed by the addition of peginterferon alfa-2a 180 µg/week to entecavir for an additional 40 weeks. The primary endpoint was HBeAg loss and HBV DNA ≤ 1,000 IU/mL 48 weeks after end of treatment (EOT). Among 28 participants from 11 sites, the median age was 37.2 (range: 22-61) years, 54% were male, and 96% were Asian. Nearly all were infected with genotype C (64%) or B (32%). Median baseline HBV DNA was 8.2 log 10 IU/mL, and ALT was 0.9 times the ULN. Although one (4%) participant cleared HBeAg, none met the primary endpoint of both HBeAg loss AND HBV DNA ≤ 1,000 IU/mL 48 weeks post-EOT. ALT elevations > 5 times the ULN occurred in eight (29%) participants, and none were associated with icterus. Forty-eight weeks posttreatment, HBV DNA rebounded to baseline levels in all participants, including the participant who lost HBeAg, and ALT values returned to near baseline levels in all but four participants. Conclusion: A lead-in strategy of 8 weeks of entecavir followed by combination peginterferon and entecavir therapy for 40 weeks had limited efficacy in adults in the IT phase of chronic HBV infection and cannot be recommended., (© 2018 by the American Association for the Study of Liver Diseases.)

The optimal management strategy for children with immune-tolerant chronic hepatitis B virus (HBV) infection remains unknown. The purpose of this clinical trial was to determine the safety and efficacy of therapy with entecavir and peginterferon in a group of children in the immune-tolerant phase of HBV infection. Children with immune-tolerant features of chronic hepatitis B (CHB) received entecavir once-daily in a dose of 0.015 mg/kg (0.5 mg maximum) for 48 weeks; peginterferon alfa-2a (180 µg/1.73m 2 subcutaneously) once-weekly was added at the end of week 8 and continued until week 48. The primary endpoint was lack of detectable hepatitis B e antigen (HBeAg) with HBV DNA levels ≤1,000 IU/mL 48 weeks after stopping therapy. Sixty children (75% female), median age 10.9 (range, 3.4-17.9) years, were enrolled. All were positive for hepatitis B surface antigen (HBsAg) and HBeAg and had high levels of HBV DNA with normal or minimally elevated levels of alanine aminotransferase (ALT). Fifty-five children completed the entire 48-week course of therapy. At 48 weeks after treatment ended (week 96), 2 children (3%) achieved the primary endpoint and were also HBsAg negative and anti-hepatitis B surface antigen antibody (anti-HBs) positive. One child was HBeAg positive but HBsAg negative at week 60; another was HBeAg negative but HBsAg positive at week 72, which were their last clinic visits. In the remaining children, serum ALT and HBV DNA levels at week 96 were similar to baseline. Thirty-seven children experienced adverse events (AEs), and 1 had a serious AE (SAE). Conclusion: The combination of entecavir and peginterferon for up to 48 weeks rarely led to loss of HBeAg with sustained suppression of HBV DNA levels in children in the immune-tolerant phase of HBV infection, and treatment was associated with frequent AEs., (© 2018 by the American Association for the Study of Liver Diseases.)